Chromatography column and maintenance method

ABSTRACT

A chromatography column and method of maintenance is described which does not require the use of a hoist or crane for disassembly. The method provides improved operator safety by reducing the need for the operator to work below a suspended or supported load within the column. Furthermore, the removal or replacement of column components is facilitated by providing access to the interior of the column and by the provision of a handling device.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional filing of U.S. patent application Ser.No. 12/863,190 filed Jul. 16, 2010, which is a filing under 35 U.S.C.§371 and claims priority to international patent application numberPCT/SE2009/000011 filed Jan. 15, 2009, published on Jul. 30, 2009, as WO2009/093952, which claims priority to patent application number0801212.2 filed in Great Britain on Jan. 23, 2008.

FIELD OF THE INVENTION

The present invention relates to chromatography columns and methods foroperating columns in industrial-scale chromatography. In particular, theinvention is concerned with chromatography columns and safer methods forperforming maintenance on such columns, such as cleaning and replacingbed supports, distributors and O-rings, without the need for heavylifting equipment such as hoists or cranes to dismantle the columns

BACKGROUND OF THE INVENTION

Chromatography columns may be used in industrial processes to purifyprocess liquids and separate substances of interest from processliquids; typical examples include large-scale preparative purificationof fine chemicals and pharmaceuticals, together with biologicalproducts.

Industrial-scale chromatography columns typically comprise a hollow,axially vertical tubular housing including a liquid inlet at the upperend and through which the buffer and substances to be separated aredispensed to the media bed located within the cavity of the tube, and aliquid collecting system at the lower end for collecting substances andbuffer. The particulate chromatographic media or bed through which thebuffer fluid and/or substances to be separated and purified percolatesis located between the liquid inlet and collecting system.

An adapter assembly is typically affixed to the upper end of the tubularhousing and a base assembly to the lower end where it is bolted to thebottom flanges. Each of these assemblies typically comprises a strongbacking plate and a distributor which further supports a bed support: abed support is a layer of mesh, filter, sinter, screen or otherfluid-permeable media-retaining material which permits process liquidflow into and out of the chromatography bed space or cavity whileretaining the bed of particulate medium. To provide adjustability andcontrol of the bed height and bed compression, the adapter assembly istypically made in the form of a piston or sliding adapter in the columntube interior. After the column is charged with bed media, typicallythrough a nozzle, the adapter may be forced toward the bottom of thetube to compress or pressurize the media bed. Generally the baseassembly is a fixed structure which is bolted against the bottom flangeof the column tube but, in some instances, may also be in the form of amovably slidable piston or adapter.

The backing plate of the base assembly generally acts as a support forthe column, being itself supported on legs or some other standarrangement which allows clearance for outlet pipe work projectingbeneath the base assembly.

When such a column requires maintenance to, or cleaning of, internalcomponents, such as the valves, seals, meshes/screens, distributionsystems etc., heavy lifting gear such as a crane or hoist is necessaryto lift the upper end/adapter assembly away from the column tube and thecolumn tube away from the lower end/base assembly as these assembliescan weigh in excess of three tons. The use of heavy overhead liftingequipment to disassemble the column in order to carry out internalmaintenance is not desirable. Operator safety is obviously a concernwhen heavy equipment is lifted overhead and technicians exposed below.Furthermore, alignment structures are required to keep the column andits base/adapter assemblies axially aligned as they are separated fromeach other, to avoid damage to the precision components.

The presence of such alignment and lifting structures imposessignificant obstructions around the tube and need to be carefully laidout to provide sufficient clearance at some point of the circumferencefor insertion/removal of the internal components. Furthermore, therequirement to use heavy lifting equipment imposes constraints onhousing such columns, sufficient overhead space and support beingrequired to accommodate hoists or cranes. As many chromatography columnsare now run in “clean” environments under GMP, to avoid microbiologicalcontamination, where it is extremely difficult to accommodate overheadequipment, the requirement of moving the column to another room fordisassembly and maintenance is problematic. This problem is exacerbatedby the need to clean and verify the column before returning it for useto the clean environment. The presence of hoists or cranes in GMPfacilities used for biopharmaceutical manufacturing is thus highlyundesirable for the above mentioned reasons, together with the fact thatthese machines shed particulate matter, in the form of dirt, duringtheir operation and maintenance.

U.S. Pat. No. 6,736,974 addresses some of the above problems byproviding a column which is capable of lifting the adapter assemblyabove the column tube and/or raising the column tube above the baseassembly by means of an hydraulic system which is integral to thecolumn.

However, the system described in U.S. Pat. No. 6,736,974 has significantdisadvantages associated with it by virtue of its design. As can be seenfrom FIGS. 4 and 5 of U.S. Pat. No. 6,736,974 and described in column 4,lines 63-66 of that document, in order to remove the distributor plate(31) and/or mesh (28/60) from the interior of the column, the operatormust work within the centre of the drum (18) to access and remove thefixing nut (30) which secures these component parts. As industrialcolumns typically have diameters ranging from about 200 mm to 2000millimetres, this means that the operator must work below a suspended orsupported load to unscrew the nut. This clearly poses a significantsafety risk to the operator, particularly where the operator's arm orhead is exposed below the suspended or supported load.

Furthermore, once the column tube/cylinder or adapter assembly has beenraised from the base assembly or tube, respectively, removal of theheavy bed support and/or distributor from the column can only beaccomplished by tilting the bed support or distributor at an angle tonegotiate the hydraulic drive pistons or safety rods. This can clearlybe seen from, for example, FIGS. 3, 4 and 5 in which the distancebetween any two safety rods (69) or between any two hydraulic pistons(36) is less than the diameter of the mesh (28/60) or distributor plate(31). The same problem would exist for the base or adapter bed support(not shown). Removal of these internal components, which could weigh inexcess of 100 kg, requires considerable manhandling by the operator andnecessitates their being exposed below the suspended column or adapterassembly. Once again, this represents a significant safety risk for theoperator.

The task of physically removing the heavy bed support or distributor, asdescribed in U.S. Pat. No. 6,736,974, must be carried out by anoperator, there being no disclosure of the use of any lifting aid toassist in this task. The configuration of the hydraulic pistons and thesafety rods, and the need to tilt the bed support and/or distributor inorder to avoid hitting these supporting structures in withdrawing thesecomponents from the column, would require the design of a bespokelifting device.

Furthermore, the method described in U.S. Pat. No. 6,736,974,necessitates raising the column tube/cylinder or adapter assembly fromthe base assembly or tube, respectively, a predetermined distancegreater than three inches in order to carry out maintenance of thecolumn, distances greater than six inches and most preferably abouttwelve inches being specified.

WO 2005/056156 (Euroflow (UK) Limited) also discloses a column which canbe accessed for maintenance without the need for a crane or hoist. Thecolumn is designed such that the tube and the base assembly can beseparated by means of hydraulic drive cylinders to provide an accessspace between them to conduct maintenance or service on the baseassembly. The piston of the adapter assembly can be advanced through thecolumn tube to expose it at the open end of the column tube, i.e. in thespace between the tube and the base assembly, for maintenance.

However, as is evident from this document (for example, FIGS. 19 and 20and related description on page 23) access to release the fasteningscrews retaining the bed support or mesh in place is provided by thespace between the tube and the base assembly. Removal of the bed supportnecessitates the operator being exposed to a suspended load whileretaining screws are removed. Furthermore, the distance between any twodrive cylinders for maintenance access is less than the diameter of thebed support (see, for example, FIG. 7), which requires the operator tomanhandle and tilt the bed support when removing or replacing it.Maintenance of the column thus imposes a significant safety risk for theoperator.

Accordingly, a need exists to improve the maintenance methods availablefor chromatography columns by providing columns which are safer andeasier for operators to use and which do not expose them to a suspendedor supported load, thereby reducing the risk of operator error andinjury.

SUMMARY OF THE INVENTION

The present invention recognises and addresses these needs and others.

In a first aspect of the present invention, there is provided a methodfor conducting maintenance on a chromatography column comprising thesteps of:

-   -   a) providing a chromatography column comprising;        -   a dispersion system comprising a nozzle including a mobile            phase pathway connected to a liquid inlet;        -   a tube with an adapter assembly connected to a drive system,            said adapter assembly moveable within a cavity of said tube            in an operational mode;        -   the adapter assembly comprising a distributor and a bed            support fastened to each other by releasable fixing means,        -   said drive system comprising one or more cylinders;        -   a collection system opposing the dispersion system; and        -   one or more seals;    -   b) disconnecting the adapter assembly from the tube;    -   c) lifting the adapter assembly a distance of no more than three        inches or seventy six millimetres above the tube with the drive        system to provide a gap for access therebetween;    -   d) unfastening the bed support from the distributor by releasing        the fixing means without accessing said gap;    -   e) removing the bed support from the column;    -   f) conducting maintenance on the column and/or the bed support        and/or said one or more seals;    -   g) returning the bed support to the column and fastening the bed        support to the distributor; and    -   h) lowering the adapter assembly with the drive system to an        operational position within the tube and reconnecting the        adapter assembly to the tube.

The gap provided for access between the adapter assembly and the tube isno more than three inches or seventy six millimetres in height in orderto permit removal of the bed support from the column or return thereto.In one aspect, the gap is no more than two inches or fifty millimetresin height to allow access to the column. In another aspect, the gap isless than two inches or fifty millimetres in height. In a furtheraspect, the gap is less than one inch or twenty five millimetres inheight. In yet another aspect the gap is at least 0.4 inches or 10millimetres in height. Restriction of the gap height to less than threeinches or seventy six millimetres prevents the operator from workingbeneath the raised adapter assembly and being physically exposed to thesuspended weight.

In a preferred aspect, the fixing means are releasable from the exteriorface of the distributor. This further reduces the exposure of theoperator to a suspended or supported load as they do not need to enterthe gap.

In a particularly preferred aspect, the drive system comprises at leasttwo cylinders and the distance between any two said cylinders formaintenance access is greater than the diameter of the bed support. Thispermits the use of a handling device to support and remove or replacethe bed support and/or distributor from/to the column.

Preferably cylinders are externally mounted to the column. Thisfacilitates greater spacing between the cylinders. More preferably, eachsaid cylinder is independently removable from the column.

Preferably, the step of removing the bed support is carried out withoutsubstantially tilting the bed support. This reduces operator exposurebeneath the suspended load and facilitates manhandling and/or mechanicalhandling of the bed support. The term ‘without substantially tilting’ asused herein means ‘tilting at an angle of no more than 5° to thehorizontal’.

More preferably, the step of removing the bed support involves use of ahandling device. More preferably, the handling device comprises at leastone arm and the method comprises supporting the bed support on oraffixing the bed support to at least one arm of the handling device.

Optionally, the step of conducting maintenance on the column furthercomprises removing the distributor without substantially tilting saiddistributor. The term ‘without substantially tilting’ as used hereinmeans ‘tilting at an angle of no more than 5° to the horizontal’. Itwill be understood that the distributor and the bed support could beremoved together and at the same time.

Preferably, the column further comprises a locking system, the methodfurther comprising the step of locking the adapter assembly with saidlocking system after lifting the adapter assembly no more than threeinches or seventy six millimetres above the tube with the drive system.This provides for greater operator safety.

According to a second aspect of the present invention, there is provideda method for conducting maintenance on a chromatography columncomprising the steps of:

-   -   a) providing a chromatography column comprising        -   a dispersion system comprising a nozzle including a mobile            phase pathway connected to a liquid inlet;        -   a tube with an adapter assembly and a base assembly            connected to a drive system, said adapter assembly moveable            within a cavity of said tube in an operational mode;        -   the base assembly comprising a distributor and a bed support            fastened to each other by releasable fixing means,        -   said drive system comprising one or more cylinders;        -   a collection system opposing the dispersion system; and        -   one or more seals;    -   b) releasing the tube from the base assembly;    -   c) lifting the tube and the adapter assembly no more than three        inches or seventy six millimetres above the base assembly with        the drive system to provide a gap for access therebetween;    -   d) unfastening the bed support from the distributor by releasing        the fixing means without accessing said gap;    -   e) removing the bed support from the column;    -   f) conducting maintenance on the column and/or the bed support        and/or said one or more seals;    -   g) returning the bed support to the column and fastening the bed        support to the distributor; and    -   h) lowering the tube and the adapter assembly with the drive        system and reconnecting the tube to the base assembly.

The gap provided for access between the tube and adapter assembly andthe base assembly is no more than three inches or seventy sixmillimetres in height in order to permit removal of the bed support fromthe column or return thereto. In one aspect, the gap is no more than twoinches or fifty millimetres in height to allow access to the column Inanother aspect, the gap is less than two inches or fifty millimetres inheight to allow access to the column. In a further aspect, the gap isless than one inch or twenty five millimetres in height. In yet anotheraspect, the gap is at least 0.4 inches or ten millimetres in height.Restriction of the gap height to less than three inches or seventy sixmillimetres prevents the operator from working beneath the raisedadapter assembly and tube and thus from being physically exposed to thesuspended weight.

Preferably, the fixing means are releasable from the exterior face ofthe distributor. This further reduces the exposure of the operator to asuspended load as they do not need to enter the gap.

Preferably, the cylinders are externally mounted to the column Thisfacilitates greater spacing between the cylinders. More preferably, eachsaid cylinder is independently removable from the column

Preferably, the distance between any two said cylinders for maintenanceaccess is greater than the diameter of the bed support. This permits theuse of a handling device to support and remove or replace the bedsupport and/or distributor from/to the column. Maintenance access is theaccess to the column and its component parts such as the bed supportand/or distributor which is required in order to carry out maintenanceor service.

Preferably, the step of removing the bed support is carried out withoutsubstantially tilting the bed support. This reduces operator exposurebeneath the suspended load and facilitates manhandling and/or mechanicalhandling of the bed support. The term ‘without substantially tilting’ asused herein means ‘tilting at an angle of no more than 5° to thehorizontal’.

Preferably, the step of removing the bed support involves use of ahandling device. More preferably, the handling device comprises at leastone arm and the method comprises supporting or affixing the bed supporton at least one arm of the handling device. More preferably, the methodcomprises releasably affixing the outer rim of the bed support to atleast one arm of said handling device.

Optionally the step of conducting maintenance on the column furthercomprises removing the distributor without substantially tilting saiddistributor. The term ‘without substantially tilting’ as used hereinmeans ‘tilting at an angle of no more than 5° to the horizontal’. Itwill be understood that the distributor and the bed support could beremoved together and at the same time.

Preferably, the column further comprises a locking system, the methodfurther comprising the step of locking the adapter assembly and the tubeabove the base assembly with said locking system after lifting saidadapter assembly and the tube no more than three inches or seventy sixmillimetres above the base assembly with the drive system. This providesfor greater operator safety.

According to a third aspect of the invention, there is provided achromatography column comprising:

a dispersion system and a nozzle including a mobile phase pathwayconnected to a liquid inlet;

a tube with an adapter assembly and a base assembly connected to a drivesystem having at least one cylinder,

said adapter assembly moveable within a cavity of said tube in anoperational mode;

the adapter assembly comprising a distributor and a bed support fastenedto each other by releasable fixing means;

the base assembly comprising a distributor and a bed support fastened toeach other by releasable fixing means;

a collection system opposing the dispersion system; and

one or more seals;

the fixing means fastening the distributor and bed support of theadapter assembly or the base assembly to each other are releasable fromthe exterior face of the distributor, wherein the adapter assembly isdisconnectable from the tube to allow lifting by the drive system inorder to provide a gap for maintenance access of no more than threeinches or seventy six millimetres; andthe tube and the adapter assembly are disconnectable from the baseassembly to allow lifting by the drive system to provide a gap formaintenance access of no more than three inches or seventy sixmillimetres.

Preferably, the drive system comprises at least two cylinders and thedistance between any two said cylinders for maintenance access isgreater than the diameter of the bed support. This permits the use of ahandling device to support and remove or replace the bed support and/ordistributor from/to the column Maintenance access is the access to thecolumn and its component parts such as the bed support and/ordistributor which is required in order to carry out maintenance orservice.

The gap provided for access between the adapter assembly and the tube,or between the tube and the adapter assembly and the base assembly, isno more than three inches or seventy six millimetres in height in orderto permit removal of the bed support and/or the distributor from thecolumn or return thereto. In one aspect, the gap is no more than twoinches or fifty millimetres in height to allow access to the column. Inanother aspect, the gap is less than two inches or fifty millimetres inheight. In a further aspect, the gap is less than one inch or twentyfive millimetres in height. In yet another aspect, the gap is greaterthan 0.4 inches or ten millimetres in height. Restriction of the gapheight to less than three inches or seventy six millimetres prevents theoperator from working beneath the raised adapter assembly and thus frombeing physically exposed to the suspended weight.

Preferably, the drive means comprises at least two hydraulic cylindersand most preferably three hydraulic cylinders. Other drive meansinclude, for example, electrical or pneumatically powered cylinders.

Preferably, the drive means is external to the column.

Preferably, the column additionally comprises a locking system forsecuring the raised adapter assembly above the tube and/or securing theraised tube and adapter assembly above the base assembly. This improvesoperator safety.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows an embodiment of a column known in the art in a firstmaintenance position in cross sectional view.

FIG. 2 is a cross sectional view showing the same embodiment of thecolumn of FIG. 1 in a second maintenance position.

FIG. 3 is a schematic exploded front view of an embodiment of thepresent invention.

FIG. 4 a is a schematic front view of a column in accordance with theinvention; FIG. 4 b is a side sectional view of the column of FIG. 4 a;and FIG. 4 c is a top plan view of the column of FIG. 4 a.

FIG. 5 a is a front perspective view showing the adapter assembly raisedand secured into position to provide a gap for access; FIG. 5 b showsremoval of the fastening means securing the distributor and bed support.

FIG. 6 is a perspective view of a handling device used to remove/inserta distributor or a bed support from/into a column in accordance with theinvention.

FIG. 7 a and FIG. 7 b are perspective views of the column of FIG. 5showing the removal of securing rods which fasten the bed support to thedistributor.

FIG. 8 a, FIG. 8 b and FIG. 8 c are perspective views showing theremoval of the bed support from the column.

FIG. 9 a is a perspective view of a column with an inset showing alocking system in accordance with the invention; FIG. 9 b shows thecolumn tube raised above the base and in the process of being lockedinto position.

FIG. 10 is a perspective view of a column with the column tube raisedand locked into position in readiness for maintenance.

FIG. 11 a and FIG. 11 b illustrate the process of removing the bedsupport from the column using a handling device.

FIG. 12 shows the bed support having been removed from the column inreadiness for maintenance.

FIG. 13 is a perspective view of the column of FIGS. 10 and 11 with thecolumn tube lowered awaiting bolting to the base.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is concerned with a method and apparatus forenabling maintenance within a chromatography column. FIG. 1 shows acolumn 10 known in the art and described in U.S. Pat. No. 6,736,974which permits maintenance within a chromatography column without theneed for a hoist or crane. The column 10 comprises an elongated hollowcylindrical housing 12, or tube, having a dispersion system 14 at thetop and a collection system 16 at the bottom. The dispersion system 14includes a cylindrical drum 18 having an upper cylindrical plunger heador adapter 20 formed at the lower or interior end (i.e. interior to thecolumn). The adapter 20 is normally disposed within the upper portion oftube 12 such as is illustrated in the first operational position ofFIG. 1. The adapter 20 may be moved by a drive system 34 such as thehydraulic arrangement shown in FIG. 1. The movement of the adapter 20allows for the compression of chromatography media in order to produce apacked media bed of the optimum height within the column; a cavity 22 isformed between the dispersion and collection systems 14, 16 and/orbetween the adapter 20 and the base 64.

The dispersion system 14 may include a mobile phase pathway connected toa liquid inlet 24 together with an inlet manifold 26 to distributeincoming liquid throughout a top portion of a media bed contained withinthe cavity 22. A bed support (or inlet screen) 28 or filter is attachedto the adapter 20 by connectors and/or by an inner clamp nut 30 which isaccessible from the cavity 22. The bed support 28 may be removed formaintenance purposes by release of the clamp nut 30; the distributorplate 31 may also be removable (see U.S. Pat. No. 6,190,560 for adescription of a distributor plate design).

A drive system is used to move the adapter 20 in an operational mode.The drive system is comprised of at least one and preferably three ormore, drive cylinders 34. The drive cylinders 34 move drive pistons 36which are coupled to the drum 18. A portion of the drive pistons 36 mayby threaded 38 to allow for the drive piston 36 to connect or couple toconnection arms 40 at specific locations relative to the drive piston 36such as with nuts 42, 44.

FIG. 1 shows a first maintenance position of the adapter 20 wherein theadapter 20 is raised a predetermined distance from a top 54 of thecavity 22 within the cylinder by means of the drive system 34 and piston36. The operator is thereby provided access with a hand to the centre ofthe drum 18 to release or affix nut 30 which retains the distributorplate 31 and bed support 28 to the adapter 20. The distributor plate 31and or/bed support 28 may then be removed for maintenance. These arethen replaced by affixing them to the adapter 20 and the adapter 20 maybe lowered to return to an operational mode, nuts 42, 44 being reset toa proper operational configuration, if necessary.

In order to perform a second maintenance operation, such as removal ofthe lower bed support (or screen) 160 which is typically positioned sothat its outer edge 162 is between the tube 112 and the collectionsystem 116, the tube 112 may be raised by the drive system asillustrated in FIG. 2. The bolts which normally secure the tube 112 tothe base 164 are removed, and the nuts 142, 144 may be coupled to thepiston 136 to drive the tube 112 along with the drum 118 upwards asshown. A gap is thus provided which allows access for an operator toloosen nut 132, which affixes the bed support 160 to the base 164, andremove the bed support 160 for maintenance. Once maintenance has beencompleted, the bed support 160 is replaced, affixed by nut 132 to thebase 164 by the operator, and the process reversed to lower tube 112 andthe drum 118 into an operational position.

The present invention will now be described with reference to FIGS. 3 to13; FIGS. 3 to 8 relate to providing access to the upper adapterassembly and FIGS. 9 to 13 to providing access to the base assembly formaintenance.

FIG. 3 is a schematic exploded front view of a column in accordance withthe invention. The column is made of strong, inert materials such asstainless steel and other materials which are suitable for use in a GMPenvironment typical of the pharmaceutical industry. The column 210 issupported on legs 204 having feet 206 which are adjustable in order tomodify the height and/or the level of the column The legs 204 supportthe column 210 which comprises a cylindrical housing or tube 212separating a base assembly 263 at one end from an adapter assembly 215at the other. The tube 212 may typically be made from stainless steel,or other strong, inert materials. Adjacent to the adapter assembly 215is a dispersion system comprising a nozzle 211 which includes a mobilephase pathway, for the introduction of buffer or other suitable mobilephase liquids or chemicals/materials to be separated, and a liquid inlet209. The tube 212 may be connected to the adapter assembly 215 and baseassembly 263 by a drive system having one or more cylinders 234. Thedrive system may be a hydraulic system, as shown, or may be powered byother suitable means, such as pneumatic or electrical means. The adapterassembly 215 is moveable within a cavity 222 of the tube 212 in anoperational mode, for example, to pack or compress the bed ofchromatographic media used to effect chromatographic separation ofchemicals within the column The adapter assembly 215 comprises anadapter flange 217, one or more distance pillars 219, a backing plate220 made typically of stainless steel, a distributor 231 which may takethe form of a plate having many channels to effect the even distributionof liquids, and a bed support 228 comprising a screen or mesh or filterand optionally a sealing ring (e.g. 229). The bed support may be made ofan inert plastic or metal material such as stainless steel. Thedistributor 231 and bed support 228 are fastened to each other byreleasable fixing means (not shown). Typical releasable fixing meansinclude, but are not limited to, a screw, a nut or a clamp. The fixingmeans (not shown) may only be accessed and thus released from theexterior face of the distributor 231 or backing plate 220, that is theface of the plate furthest away from the cavity 222. In the presentexample, the nozzle 211 must first be removed to provide access to thefixing means (not shown). Additional releasable fixing means, accessiblefrom the exterior face of the backing plate, may optionally be employedto fasten the backing plate, distributor and bed support together. Thesefixing means can take the form of bolts inserted through correspondingholes around the perimeter of the components. Access from the exteriorface of the backing plate or distributor avoids unnecessary exposure ofthe operator to a suspended or supported load within the column.

The base assembly 263 comprises a distributor 266 and a bed support 268and optionally a backing plate 264 fastened to each other by releasablefixing means 269. The bed support 268 comprises a screen or mesh orfilter and optionally a sealing ring (e.g. 274). The bed support may bemade of an inert plastic or metal material such as stainless steel.Releasable fixing means 269 are, for example, a screw, a nut, a bolt ora clamp; it will be appreciated that other releasable fixing means arealso possible. As can be seen from the figure, the fixing means 269secures bed support 268 and the distributor 266 through a central holein each component. The fixing means 269 is only accessible and maytherefore only be released from the exterior face of the distributor266. In FIG. 3, nozzle 272 must first be removed to provide access torelease fixing means 269. Additional releasable fixing means, accessiblefrom the exterior face of the backing plate, may optionally be employedto fasten the backing plate, distributor and bed support together. Thesefixing means can take the form of bolts inserted through correspondingholes around the perimeter of the components. Access from the exteriorface of the backing plate 264 avoids operator exposure beneath asuspended load, were access only to be available from within theinterior of the column.

It will be understood that separation of chemical or biologicalmaterials on the column, when the tube 212 is full of chromatographicmedia, can be carried out in either a downward or upward flow. Thus, ina downward flow, liquid containing chemical or biological materials tobe separated is introduced through nozzle 211 and moves in a downwarddirection through the bed of media, to be collected in the collectionsystem at the base of the column via an outlet port (not shown). Inupward flow mode, liquid containing materials to be separated isintroduced via the bottom nozzle 272 and flows upwards through the mediabed to be collected at the top of the column via an outlet port (notshown). In the interests of clarity, the maintenance or servicing of thecolumn will be described in downward flow mode.

In order to conduct maintenance on the adapter assembly 215 ordistributor 231, the adapter assembly 215 is disconnected from thecolumn tube 212 by unscrewing the nuts which join the adapter flange 217to the upper column flange 213 a. The drive system then raises theadapter assembly 215 a distance of no more than three inches or seventysix millimetres, typically a distance of no more than two inches orfifty millimetres by means of cylinders 234 to allow for access to theinterior of the column for maintenance or service. The adapter assembly215 is locked into position using the locking system 270 by means ofplungers 237 which are inserted through aligned holes in the cylinderbracket 236, cylinder 234 and assembly 215. In this secured position,the adapter bed support and/or the distributor may be removed from thecolumn for maintenance once the fixing means are released, release beingeffected by removal from the exterior face of the column followingremoval of the nozzle 211 as described above. Once maintenance has beencarried out on the column (e.g. the bed support 228 has been replaced),the column 210 is made operational again by reversing the aboveprocedure: the adapter assembly 215 is released from its securedposition by removal of the plungers 237 and lowered by use of cylinders234 to be reconnected to the column tube 212 by replacing the nuts whichjoin the adapter flange 217 to the upper column flange 213 a.

Maintenance or service is carried out on the bottom distributor 266 orbase assembly 263 by releasing the tube 212 from the base assembly 263and lifting the tube 212 and adapter assembly 215 a distance of no morethan three inches or seventy six millimetres, typically a distance of nomore than two inches or fifty millimetres, with the aid of the drivesystem. The bolts on the lower flange 213 b of the column tube 212 whichjoin it to the bottom backing plate 264 are removed. The column tube 212and adapter assembly 215 are then lifted by means of the drive cylinders234. The tube 212 and upper adapter assembly is secured in position bythe locking system 270 above the base with the cylinder brackets 236 byinserting a plunger (not shown) through holes aligned in the locking pin238 and bracket 236.

The bottom nozzle 272 is then disconnected from the back plate 264 anddistributor 266. The nozzle 272 is removed together with the distancering 235, to allow access to release the fixing means 269 which may bein the form of a nut. The nut 269 is removed from the exterior face ofthe distributor 266, i.e. the face distant from the cavity 222, and thuseliminates operator exposure to a suspended or supported load. Ifadditional releasable fixing means, such as bolts inserted through thebacking plate, distributor and bed support as described above arepresent, these must be removed from the exterior face of the backingplate. The interior of the column may now be accessed for maintenance orservice, such as the replacement or cleaning of the bed support 268and/or O-rings. To return the column to an operational mode, the aboveprocedure is reversed.

FIG. 4 a is a schematic front view of a column in accordance with theinvention. The column 310 is supported on legs 304 and has a baseassembly 363 separated from an adapter assembly 315 by a tube 312. Thesecomponents are made of strong, inert materials which are approved forGMP within the pharmaceutical industries, such as stainless steel. Inthe figure, the base assembly 363 and adapter assembly are connected toa drive system which takes the form of three hydraulic cylinders 334. Itwill be understood that in other embodiments, different drive systemsmay be used to raise and lower the column, such as those powered bycompressed air or electricity. Furthermore, it is not essential thatthree cylinders are used, in some cases one being sufficient. The column310 has a top nozzle 311 and a bottom nozzle for the introduction ofliquids into the column An electrical unit 378 for controlling the drivesystem is also shown.

FIG. 4 b is a side sectional view of the column of FIG. 4 a showing oneof the hydraulic cylinders 334 in cross section. The cavity 322 forcontaining the bed of chromatographic media can be seen in crosssection. The liquid inlet 305, 375 and outlet 306, 376 of the top 311and bottom 372 nozzle are shown, for the introduction and removal ofliquids from the column 310. The cylinder 334 is connected to the baseassembly (seen here comprising backing plate 364, distributor 366 andbed support 368) and the adapter assembly 315 (seen here comprisingbacking plate 320, distributor 331 and bed support 328).

FIG. 4 c is a top plan view of the column of FIG. 4 a which shows thethree hydraulic cylinders 334 and nozzle 311 with liquid inlet 305 andoutlet 306.

To raise the adapter assembly 315 for maintenance purposes, the nutsunder the upper column flange, which join the adapter 315 and columnflange 313 a, are loosened and removed. The drive system then lifts theadapter assembly 315 a distance of no more than three inches or seventysix millimetres, typically a distance of no more than two inches orfifty millimetres, by means of the hydraulic cylinders 334. The adapterassembly 315 is raised until holes in the cylinder bracket (not shown),hydraulic cylinders 334 and the adapter assembly 315 are aligned andlocked into position with plungers (not shown) to secure the assembly inthe service or maintenance position (see FIG. 3).

FIG. 5 a is a front perspective view showing the adapter assembly 415raised and secured into position to provide a gap 427 for access to theinterior of the column for service or maintenance. The gap 427 isclearly shown in the figure for illustrative purposes but it would be nomore than three inches or seventy six millimetres and typically no morethan two inches or fifty millimetres in size to prevent the operatorinadvertently reaching into it and exposing his/her arm to a heavysuspended load. The column 410 has a drive system comprising threehydraulic cylinders 434. The adapter bed support 428, the distributor431 and the backing plate 420 are now visible; the bed support 428 canbe unfastened from the distributor 431 by releasing the fixing means(not shown) without accessing the gap 427. In order to describe thisprocess, reference is made to FIG. 4 in that the nozzle 311 is firstremoved to provide access to remove the retaining nut (not shown) whichsecures the bed support 328 to the distributor 331 without accessing thegap 427. The fixing nut is removed from the exterior face of thedistributor 331.

FIG. 5 b shows release of the fixing means from the backing plate 420side of the adapter assembly using a spanner 446. The fixing means (inthe form of a retaining nut, obscured by the spanner) secures theadapter bed support to the distributor.

The bed support 428 is heavy and requires the use of a special handlingdevice to lift it once it has been separated from the adapter assembly.

An embodiment of the handling device 580 is shown in FIG. 6. The device580 is in the form of a trolley or cart with a central pillar 581supported on frame 582 having legs 583. The device 580 is made ofstrong, inert materials; such materials include, but are not limited to,stainless steel and other materials which are suitable for use in a GMPenvironment typical of the pharmaceutical industry. Extendable arms 585a, b, c project from the pillar 581 and can be raised or loweredrelative to the pillar 581 by mechanical or other means. In theembodiment shown, the arms 585 a, b, c are raised or lowered by a manualjacking mechanism (not shown) adjacent to the handle 584 which providesthe means to steer or control the device. The arms 585 a, b, c aredesigned to bear the weight of the distributor or bed support and areextendable to the diameter of these components. While the embodimentshown has three arms 585 a, b, c, it will be understood that the deviceis not so limited and that other embodiments may have less than or morethan three arms (e.g. one, two, four, five) depending on the individualdesign. Holes 587 a, b, c at the extremities of the arms 585 a, b, c areprovided for bolting or securing of the distributor and/or bed supportto the arms for safety, particularly during transport. Pads (not shown)may be fitted to the arms 585 a, b, c to minimise any risk of damage tothe bed support/distributor when these components come into contact withthe arms. A raised, central element, 588 (typically of conical shape)for receipt of the central hole in the bed support or distributorprovides a means for centralising these components on the arms 585 a, b,c of the device 580. This element 588 may be fitted on either, or both,the upper or under side of the point where the arms 585 a, b, cintersect. In operation, the distributor and/or bed support is eithersuspended from the arms 585 a, b, c or supported on the arms. Pivotalwheels 586 allow easy movement and manoeuvrability of the handlingdevice 580. In the embodiment shown, the movement of the device 580 andthe raising/extension of the arms 585 a, b, c are by manual means, butit will be understood that other embodiments are possible whichincorporate powered systems (e.g. electrical, pneumatic or hydraulicsystems) to drive the device 580 and lift/lower the arm 585. It willalso be understood that in other embodiments of the handling device (notshown), arm 585 a is capable of pivoting or rotation around pillar 581to enable the arms 585 b and c to access a narrow gap between any twocylinders (e.g. 434 of FIG. 5 a) and remove/insert a bed support and/ordistributor which have a diameter which is greater than the distancebetween any two cylinders in the column (e.g. 434 of FIG. 5 a).

Other embodiments of the handling device are possible, for example inwhich the holes 587 b, c are configured to align with correspondingholes in the side of the bed support or distributor when the arms 585 b,c contact the outer rim of these components, thereby allowing affixmentof the bed support or distributor to the arms simply by means ofthreading screws into the aligned holes.

The operation of the device 580 in removing the bed support is shown inFIGS. 7 to 9.

FIG. 7 a and FIG. 7 b are perspective views of the column of FIG. 5showing the handling device of FIG. 6 supporting the bed support 628 onone or more arms 685. The arms 685 are raised into position below thebed support 628, care being taken not to damage the bed support bypositioning the pads (not shown) on the arms 685 of the handling device680 under the outer rim of the bed support and then gently raising thearms 685 up to the bed support. Once the arms 685 are in position, thenuts on the threaded rods 633 that go through the back plate 620 anddistributor 631 into the outer perimeter of the bed support 628 areloosened and the bed support can be removed on the handling device. Therods 633 are initially loosened with a spanner and finally removed byhand. As can be seen from the figures, the removal of the rods 633 iscarried out from the exterior face of the backing plate 620 withoutaccessing the gap and thus without exposing the operator to a suspendedor supported overhead weight.

FIG. 8 a and FIG. 8 b are perspective views showing the removal of thebed support 728 on the handling device 780 from the column 710. In FIG.8 a the bed support 728, supported on the arms 785 of the device 780, isremoved from the column 710 without substantially tilting the support728. The device 780 can then be moved away from the column (FIG. 8 b)and the arms 785 lowered in order that the bed support 728 can becleaned or replaced. Maintenance or servicing the column may now becarried out as required. For example, the bed support 728 may be cleanedor replaced, O-rings replaced and/or the distributor 731 may also beremoved for cleaning.

FIG. 8 c is a perspective view showing the removal of the bed support728 from a column 710 using a different embodiment of a handling device780. The bed support 728 is secured or affixed to the arms 785 of thehandling device 780 by inserting bolts or screws through holes 787 inthe arms 785 of the handling device 780 into corresponding holes in therim of the bed support 728.

To return to an operational mode, the above procedure is simplyreversed. The bed support and/or distributor is returned to the columnand affixed to each other and to the backing plate, the nozzlereattached, the adapter assembly lowered and bolted to the column tube.

Access to the bottom bed support and interior of the column will now bedescribed with reference to FIGS. 9 to 13. To access the bottom bedsupport, the tube is released from the base assembly by unscrewing thebolts that join it to the base and then lifting the tube and upperadapter assembly with the hydraulic cylinders.

FIG. 9 a shows a column 810 as previously described in FIGS. 3 to 5 andFIGS. 7 and 8. The bolts on the lower flange 813 b of the column tubewhich fasten the tube 812 to the bottom backing plate 864 are loosenedand unscrewed. The column tube 812 and adapter assembly 815 are liftedby the hydraulic cylinders 834 of the drive system no more than threeinches or seventy six millimetres above the base assembly and securedinto position by the locking system 870 (see inset of FIG. 9 a showingpart of the locking system) as described previously. Plungers 837 areintroduced into the aligned holes in the locking pin 838 and bracket 836to secure the tube and adapter assembly in position (FIG. 9 b). Afterremoval of the bolts securing the tube 812 to the bottom backing plate864, maintenance can now be carried out on the column in the gap 827created by raising the tube and adapter assembly. This gap is no morethan three inches and typically no more than two inches to restrictoperator access to the gap.

FIG. 10 shows the column 910 with the tube 912 raised and mechanicallylocked to the cylinders 934 in readiness for maintenance. The bottomnozzle (not shown—see 272 in FIG. 3) is first removed from the backplate 964 by unscrewing the retaining bolts. The retaining nut (orfixing means) which fastens the bed support 968 to the distributor 966is released from the backing plate 964 side of the column 910. Ifadditional fixing means are present, such as bolts (not shown) whichfasten the bed support to the distributor and the backing plate, and arelocated on the perimeter of the backing plate, these are released fromthe backing plate face of the column.

The bed support 1068 can now be removed from the column by use of thehandling device as shown in FIG. 11 a and FIG. 11 b. The handling device(as described in FIG. 6 above) 1080 is wheeled into position where thearms 1085 are no more than three inches and typically no more than twoinches above the bed support 1068. The bed support 1068 has a number ofthreaded holes that correspond to the holes used to bolt the bed supportto the backing plate 1064. The arms 1085 of the handling device 1080have holes through which bolts are screwed into the bottom bed support1068; these holes are aligned to those of the bed support 1068 and boltsaffixed to secure the bed support to the arms 1085. Once attached, thebed support 1068 can be removed from the column by raising the arms 1085no more than three inches and typically no more than two inches and thenwheeling the handling device 1080 away from the column 1010. It will beunderstood that other embodiments of handling devices, such as thatdescribed in FIG. 8 c above, can be used to remove the bed support.

The bed support 1068 can now be cleaned or new O-rings replaced asnecessary. Generally the bed support will be moved away from the column,as shown in FIG. 12, lowered onto a surface (such as a trolley orworkbench) and released from the arms 1185 of the handling device 1180to facilitate cleaning and servicing. The distributor (1066 in FIG. 11)can also be removed and serviced in a similar manner using the liftingdevice.

Once maintenance or servicing has been completed, the column is returnedto an operational mode by simply reversing the process as describedabove. This involves replacing the bed support/and or distributor in thecolumn, affixing the components to the backing plate, reattaching thenozzle, lowering the tube and adapter assembly. FIG. 13 shows the column1210 of FIG. 11 connected to the hydraulic control unit 1290 with thetube 1212 lowered and ready to be bolted to the backing plate 1264.

While preferred illustrative embodiments of the present invention aredescribed, one skilled in the art will appreciate that the presentinvention can be practiced by other than the described embodiments,which are presented for purposes of illustration only and not by way oflimitation. The present invention is limited only by the claims thatfollow.

1-28. (canceled)
 29. A chromatography column comprising: a dispersionsystem and a nozzle including a mobile phase pathway connected to aliquid inlet; a tube with an adapter assembly and a base assemblyconnected to a drive system having at least one cylinder, said adapterassembly moveable within a cavity of said tube in an operational mode;the adapter assembly comprising a distributor and a bed support fastenedto each other by releasable fixing means; the base assembly comprising adistributor and a bed support fastened to each other by releasablefixing means; a collection system opposing the dispersion system; andone or more seals; said fixing means fastening the distributor and bedsupport of the adapter assembly or the base assembly to each other arereleasable from the exterior face of the distributor; wherein theadapter assembly is disconnectable from the tube to allow lifting by thedrive system in order to provide a gap for maintenance access of no morethan three inches or seventy six millimetres; and the tube and theadapter assembly are disconnectable from the base assembly to allowlifting by the drive system to provide a gap for maintenance access ofno more than three inches or seventy six millimetres.
 30. Thechromatography column of claim 29, wherein said drive system comprisesat least two cylinders and the distance between any two said cylindersfor maintenance access is greater than the diameter of the bed support.31. The chromatography column of claim 29, wherein the drive systemcomprises at least two hydraulic cylinders and preferably threehydraulic cylinders.
 32. The chromatography column of claim 29, whereinthe drive system is external to the column.
 33. The chromatographycolumn of claim 29, further comprising a locking system for securing theraised adapter assembly above the tube and/or securing the raised tubeand adapter assembly above the base assembly.